Leucascandrolide A is a highly cytotoxic macrolide isolated from the calcareous sponge Leucascandra caveolata. This compound exhibits a highly potent cell growth inhibitory activity in human A549 non-small lung caner cells (GI50=0.93 nM) and HCT-116 colon cancer cells (GI50=0.87 nM). Further, leucascandrolide A proves to be an effective fungistatic inhibitor in a W303 strain of yeast S. cerevisiae as well (33 mm/11.2 mg inhibition diameter per disk).
The total synthesis of leucascandrolide A has been achieved by several groups: D'Ambrosio et al., Helv. Chim. Acta, 1996, 79: 51-60; Hornberger et al., J. Am. Chem. Soc., 2000, 122:12894-95; Crimmins et al., Org. Lett., 2000, 2:597-99; Vakalopoulos et al., Org. Lett., 2001, 3, 177-180; Kozmin, Org. Lett., 2001, 3:755-58; Yang et al., Pure Appl. Chem., 2005, 77:1161-69; Yang et al., J. Am. Chem. Soc., 2002, 124: 13670-71.
Because of its extraordinary ability to inhibit both human cancer cell proliferation and yeast growth, leucascandrolide A is a potential candidate in cancer treatment. However, the complicated synthesis of leucascandrolide A remains a challenge. Access to less draconian methods for preparing this target molecule and its simplified analogs, by developing highly efficient synthesis routes for these compounds, is thus a crucial step forward in efforts to determine the mode of action of this compound in yeast and mammalian cells, and to reveal any structure-activity relationship. Such methods and synthetic analogs and intermediates are provided herein.